Document Detail

Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.
MedLine Citation:
PMID:  23354436     Owner:  NLM     Status:  MEDLINE    
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.
Vikram P Sharma; Aimée L Fenwick; Mia S Brockop; Simon J McGowan; Jacqueline A C Goos; A Jeannette M Hoogeboom; Angela F Brady; Nu Owase Jeelani; Sally Ann Lynch; John B Mulliken; Dylan J Murray; Julie M Phipps; Elizabeth Sweeney; Susan E Tomkins; Louise C Wilson; Sophia Bennett; Richard J Cornall; John Broxholme; Alexander Kanapin; ; David Johnson; Steven A Wall; Peter J van der Spek; Irene M J Mathijssen; Robert E Maxson; Stephen R F Twigg; Andrew O M Wilkie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-27
Journal Detail:
Title:  Nature genetics     Volume:  45     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-05-30     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  304-7     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
RefSeq/NC_000015;  NM_207037;  NM_207040
Export Citation:
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MeSH Terms
Acrocephalosyndactylia / complications,  genetics,  pathology
Basic Helix-Loop-Helix Transcription Factors / genetics*
Cranial Sutures / growth & development,  pathology
Craniosynostoses* / complications,  genetics,  pathology
Gene Expression Regulation, Developmental
Mice, Transgenic
Molecular Sequence Data
Nuclear Proteins / genetics*
Sequence Analysis, DNA
Transcriptional Activation
Twist Transcription Factor / genetics*
Grant Support
090532//Wellcome Trust; 093329//Wellcome Trust; 093329//Wellcome Trust; 095552//Wellcome Trust; R01 DE016320/DE/NIDCR NIH HHS; R01 DE019650/DE/NIDCR NIH HHS; R01DE016320/DE/NIDCR NIH HHS; R01DE019650/DE/NIDCR NIH HHS
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Nuclear Proteins; 0/TWIST1 protein, human; 0/Tcf12 protein, mouse; 0/Twist Transcription Factor; 136253-27-5/Twist1 protein, mouse; 142661-93-6/TCF12 protein, human
Peter Donnelly / ; John Bell / ; David Bentley / ; Gil McVean / ; Peter Ratcliffe / ; Jenny Taylor / ; Andrew Wilkie / ; Peter Donnelly / ; John Broxholme / ; David Buck / ; Jean-Baptiste Cazier / ; Richard Cornall / ; Lorna Gregory / ; Julian Knight / ; Gerton Lunter / ; Gil McVean / ; Jenny Taylor / ; Ian Tomlinson / ; Andrew Wilkie / ; David Buck / ; Christopher Allan / ; Moustafa Attar / ; Angie Green / ; Lorna Gregory / ; Sean Humphray / ; Zoya Kingsbury / ; Sarah Lamble / ; Lorne Lonie / ; Alistair Pagnamenta / ; Paolo Piazza / ; Guadelupe Polanco / ; Amy Trebes / ; Gil McVean / ; Peter Donnelly / ; Jean-Baptiste Cazier / ; John Broxholme / ; Richard Copley / ; Simon Fiddy / ; Russell Grocock / ; Edouard Hatton / ; Chris Holmes / ; Linda Hughes / ; Peter Humburg / ; Alexander Kanapin / ; Stefano Lise / ; Gerton Lunter / ; Hilary Martin / ; Lisa Murray / ; Davis McCarthy / ; Andy Rimmer / ; Natasha Sahgal / ; Ben Wright / ; Chris Yau /
Erratum In:
Nat Genet. 2013 Oct;45(10):1261

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